PROJECT SUMMARY/ABSTRACT Alterations in tissue composition are fundamental in atherogenesis, and may be detected as bone-like calcification in aorta or changes in vascularity and adipogenic phenotype in adipose tissue, both affecting cardiovascular disease. In this proposal, we will investigate the importance of the Bone Morphogenetic Proteins (BMPs) and their inhibitors in regulating adipose vascularity and composition, and how proatherogenic factors influence BMP activity. Recent discoveries have shown that BMP4 and 7 influence the development of adipose tissue. In addition, the balance between BMP4 activation and inhibition determines the extent of vascular calcification through cell differentiation. New data also suggest that the BMP balance orchestrates vascular growth and adipogenic differentiation in adipose tissue, and is therefore a likely determinant of tissue perfusion and hypoxia leading to inflammation. Aim 1 will test the hypothesis that the BMP balance orchestrates angiogenesis and adipogenesis in adipose tissue. New findings in null mice for Matrix Gla Protein (MGP), a BMP inhibitor, suggest an inverse relationship between endothelial and adipogenic differentiation regulated by BMP4, BMP7 and MGP. We will (a) determine how the BMPs and BMP inhibitors regulate endothelial and adipogenic phenotype in progenitor cells, (b) investigate how BMP and BMP inhibitors regulate angiogenesis and adipogenesis using genetically altered mice, and (c) examine if high BMP activity stimulates the endothelium to contribute adipogenic cells. Aim 2 will test the hypothesis that delivery of glucose or lipids to adipose tissue and genetic variations act on the BMP balance in adipose tissue to regulate tissue composition. We will take advantage of (a) diabetic Ins2-Akita/+ mice with normal and enhanced MGP expression, (b) fat-fed Ldlr-/- mice, and (c) adipocyte-specific Idol transgenic mice developed with Project 5 to investigate how these conditions influence adipose BMP signaling, vascularity and cell differentiation. We will also use the Hybrid Mouse Diversity Panel developed in Project 4 to examine variations in BMP, Notch (together with Project 1) and related gene expression in aorta and adipose tissue. Understanding BMP signaling in the adipose and vascular tissues may lead to new treatments aimed at cardiovascular disease.